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Abstract:

The present invention provides a PPAR γ agonist comprising, as an
active ingredient, a tricyclic compound represented by the formula (I)
##STR00001##
(wherein R1 represents lower alkyl optionally having substituent(s)
or the like, R2 and R3 are the same or different and each
represents lower alkyl optionally having substituent(s) or the like,
R4 and R5 are the same or different and each represents a
hydrogen atom or the like, Q1-Q2-Q3 represents
CH═CH--CH═CH or the like, Y represents a single bond or the like,
Z1-Z2 represents C═CR13 (wherein R13 represents a
hydrogen atom or the like), or the like, and A represents --COOH or the
like), or a pharmaceutically acceptable salt thereof and the like.

Claims:

1.-47. (canceled)

48. A method of activating peroxisome growth substance activation receptor
γ (PPARγ), which comprises administering an effective amount
of a tricyclic compound represented by the formula (I) ##STR00407##
whereinR1 represents lower alkyl optionally having substituent(s),
cycloalkyl optionally having substituent(s), lower alkoxy optionally
having substituent(s) or lower alkylsulfanyl optionally having
substituent(s), andR2 and R3 are the same or different and each
represents a hydrogen atom, lower alkyl optionally having substituent(s),
lower alkenyl optionally having substituent(s), lower alkanoyl optionally
having substituent(s), lower alkoxycarbonyl optionally having
substituent(s), lower alkylcarbamoyl optionally having substituent(s),
di-lower alkylcarbamoyl optionally having substituent(s) or aliphatic
heterocycle-carbonyl optionally having substituent(s), ora group
##STR00408## in the formula (I) is selected from the group consisting of
the following formulas (a1) to (a20) ##STR00409## ##STR00410##
##STR00411## wherein R1 is as defined above,R6 and R7 are
the same or different and each represents a hydrogen atom, halogen,
nitro, cyano, formyl, oxo, hydroxy, lower alkoxy optionally having
substituent(s), lower alkanoyloxy optionally having substituent(s), lower
alkyl optionally having substituent(s), lower alkenyl optionally having
substituent(s), lower alkanoyl optionally having substituent(s), lower
alkoxycarbonyl optionally having substituent(s), --NR9R10
(wherein R9 and R10 are the same or different and each
represents a hydrogen atom, lower alkyl optionally having substituent(s),
lower alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s) or aralkyl optionally having
substituent(s), or R9 and R10 form, together with the adjacent
nitrogen atom thereto, a nitrogen-containing heterocyclic group
optionally having substituent(s)), --CONR11R12 (wherein
R11 and R12 are the same or different and each represents a
hydrogen atom, lower alkyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s) or aralkyl optionally having
substituent(s), or R11 and R12 form, together with the adjacent
nitrogen atom thereto, a nitrogen-containing heterocyclic group
optionally having substituent(s)), aryl optionally having substituent(s),
aralkyl optionally having substituent(s), an aromatic heterocyclic group
optionally having substituent(s) or an aliphatic heterocyclic group
optionally having substituent(s), andR8 represents a hydrogen atom
or lower alkyl optionally having substituent(s),and whereinR4 and
R5 are the same or different and each represents a hydrogen atom,
halogen, hydroxy, lower alkoxy or lower alkyl,Q1-Q2-Q3
represents CH═CH--CH═CH, S--CH═CH or CH═CH--S,Y
represents a single bond, CH2, CH2CH2, CH═CH, O, S,
CH2O, OCH2, CH2S or SCH2,Z1-Z2 represents
(a) C═CR13 wherein R13 represents a hydrogen atom or lower
alkyl optionally having substituent(s), (b) CH--CR14R15 wherein
R14 and R15 are the same or different and each represents a
hydrogen atom or lower alkyl optionally having substituent(s), or (c)
N--CR16R17 wherein R16 and R17 are the same or
different and each represents a hydrogen atom or lower alkyl optionally
having substituent(s), andA represents a group selected from the group
consisting of the following formulas (b1) to (b6) ##STR00412## wherein
R18 represents lower alkyl optionally having substituent(s) or aryl
optionally having substituent(s),or a pharmaceutically acceptable salt
thereof.

49. The method according to claim 48, wherein the method of activating
PPARγ is a method for treating and/or preventing a disease related
to PPARγ.

50. The method according to claim 49, wherein the disease related to
PPARγ is a disease further related to an angiotensin II receptor.

51. The method according to claim 49, wherein the disease related to
PPARγ is a disease selected from the group consisting of type 2
diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity and hypertriglyceridemia.

52. A method of activating PPARγ and antagonizing an angiotensin II
receptor, which comprises administering an effective amount of the
tricyclic compound or the pharmaceutically acceptable salt thereof
recited in claim 48.

53. The method according to claim 52, wherein the method of activating
PPARγ is a method for treating and/or preventing a disease related
to PPARγ.

54. The method according to claim 53, wherein the disease related to
PPARγ is a disease further related to an angiotensin II receptor.

55. The method according to claim 53, wherein the disease related to
PPARγ is a disease selected from the group consisting of type 2
diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity and hypertriglyceridemia.

56. A tricyclic compound represented by the formula (IA) ##STR00413##
whereinR1A represents lower alkyl optionally having substituent(s),
cycloalkyl optionally having substituent(s), lower alkoxy optionally
having substituent(s) or lower alkylsulfanyl optionally having
substituent(s), andR2A and R3A are the same or different and
each represents a hydrogen atom, lower alkyl optionally having
substituent(s), lower alkenyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s), lower alkylcarbamoyl optionally having
substituent(s), di-lower alkylcarbamoyl optionally having substituent(s)
or aliphatic heterocycle-carbonyl optionally having substituent(s), ora
group ##STR00414## in the formula (IA) is selected from the group
consisting of the following formulas (A1) to (A20) ##STR00415##
##STR00416## ##STR00417## wherein R1A is as defined above,R6A
and R7A are the same or different and each represents a hydrogen
atom, halogen, nitro, cyano, formyl, oxo, hydroxy, lower alkoxy
optionally having substituent(s), lower alkanoyloxy optionally having
substituent(s), lower alkyl optionally having substituent(s), lower
alkenyl optionally having substituent(s), lower alkanoyl optionally
having substituent(s), lower alkoxycarbonyl optionally having
substituent(s), --NR9AR10A (wherein R9A and R10A are
the same or different and each represents a hydrogen atom, lower alkyl
optionally having substituent(s), lower alkanoyl optionally having
substituent(s), lower alkoxycarbonyl optionally having substituent(s) or
aralkyl optionally having substituent(s), or R9A and R10A form,
together with the adjacent nitrogen atom thereto, a nitrogen-containing
heterocyclic group optionally having substituent(s)),
--CONR11AR12A (wherein R11A and R12A are the same or
different and each represents a hydrogen atom, lower alkyl optionally
having substituent(s), lower alkanoyl optionally having substituent(s),
lower alkoxycarbonyl optionally having substituent(s) or aralkyl
optionally having substituent(s), or R11A and R12A form,
together with the adjacent nitrogen atom thereto, a nitrogen-containing
heterocyclic group optionally having substituent(s)), aryl optionally
having substituent(s), aralkyl optionally having substituent(s), an
aromatic heterocyclic group optionally having substituent(s) or an
aliphatic heterocyclic group optionally having substituent(s),
andR8A represents a hydrogen atom or lower alkyl optionally having
substituent(s),and whereinR4A and R5A are the same or different
and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy or
lower alkyl,Q1A-Q2A-Q3A represents CH═CH--CH═CH,
S--CH═CH or CH═CH--S,YA represents a single bond, CH2,
CH2CH2, CH═CH, O, S, CH2O, OCH2, CH2S or
SCH2,Z1A-Z2A represents (a) C═CR13A wherein
R13A represents a hydrogen atom or lower alkyl optionally having
substituent(s), (b) CH--CR14AR15A wherein R14A and
R15A are the same or different and each represents a hydrogen atom
or lower alkyl optionally having substituent(s), or (c)
N--CR16AR17A wherein R16A and R17A are the same or
different and each represents a hydrogen atom or lower alkyl optionally
having substituent(s), and(i) when Z1A-Z2A is (a)
C═CR13AA wherein R13AA represents lower alkyl optionally
having substituent(s), (b) CH--CR14AR15AA wherein R14A is
as defined above, and R15AA represents lower alkyl optionally having
substituent(s), or (c) N--CR16AAR17A wherein R16AA is
lower alkyl optionally having substituent(s) and R17A is as defined
above, andAA represents a group selected from the group consisting
of the following formulas (B1) to (B6) ##STR00418## wherein R18A
represents lower alkyl optionally having substituent(s) or aryl
optionally having substituent(s), and(ii) when Z1A-Z2A is (a)
C═CR13AB wherein R13AB represents a hydrogen atom, (b)
CH--CR14ABR15AB wherein both of R14AB and R15AB
represent a hydrogen atom, or (c) N--CR16ABR17AB wherein both
of R16AB and R17AB represent a hydrogen atom,AA represents
a group selected from the group consisting of the following formulas (B3)
to (B6) ##STR00419## wherein R18A is as defined above,or a
pharmaceutically acceptable salt thereof.

57. The tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 56, wherein the group ##STR00420## in the formula (IA)
is a group selected from the group consisting of the aforementioned
formulas (A1) to (A20).

58. The tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 56, wherein ##STR00421## in the formula (IA) is a
group selected from the group consisting of the following formulas (A4),
(A9), (A11) and (A12) ##STR00422## wherein R1A, R6A and
R7A are as defined above, respectively.

59. The tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 56, wherein ##STR00423## in the formula (IA) is a
group represented by the following formula (A4) ##STR00424## wherein
R1A, R6A and R7A are as defined above, respectively.

60. The tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 56, wherein ##STR00425## in the formula (IA) is a
group represented by the following formula (A12) ##STR00426## wherein
R1A, R6A and R7A are as defined above, respectively.

61. The tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 56, wherein Z1A-Z2A is C═CR13AA
(wherein R13AA is as defined above), CH--CHR15AA (wherein
R15AA is as defined above), or N--CR16AAR17A (wherein
R16AA and R17A are as defined above, respectively).

62. The tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 56, wherein AA is the following formula (B3)
##STR00427##

63. The tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 56, wherein Q1A-Q2A-Q3A is
CH═CH--CH═CH.

64. The tricyclic compound or the pharmaceutically acceptable salt thereof
according to claim 56, wherein YA is CH2CH2 or CH2O.

65. A pharmaceutical composition comprising the tricyclic compound or the
pharmaceutically acceptable salt thereof recited in claim 56 as an active
ingredient.

66. A method of activating PPARγ, which comprises administering an
effective amount of the tricyclic compound or the pharmaceutically
acceptable salt thereof recited in claim 56.

67. A method of activating PPARγ and antagonizing an angiotensin II
receptor, which comprises administering an effective amount of the
tricyclic compound or the pharmaceutically acceptable salt thereof
recited in claim 56.

68. The method according to claim 66, wherein the method of activating
PPARγ is a method for treating and/or preventing a disease related
to PPARγ.

69. The method according to claim 68, wherein the disease related to
PPARγ is a disease further related to an angiotensin II receptor.

70. The method according to claim 68, wherein the disease related to
PPARγ is a disease selected from the group consisting of type 2
diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity and hypertriglyceridemia.

71. A method of antagonizing an angiotensin II receptor, which comprises
administering an effective amount of the tricyclic compound or the
pharmaceutically acceptable salt thereof recited in claim 56.

72. The method according to claim 71, wherein the method of antagonizing
an angiotensin II receptor is a method for treating and/or preventing a
disease related to an angiotensin II receptor.

73. The method according to claim 72, wherein the method for treating
and/or preventing a disease related to an angiotensin II receptor is a
method for treating and/or preventing hypertension.

[0002]PPARγ is a member of the nuclear hormone receptor superfamily,
and plays an important role in adipocyte differentiation. Hypertrophic
adipocytes secrete large amounts of a cytokine such as TNF-α, and
free fatty acid which induce insulin resistance. On the other hand,
thiazolinedione derivatives such as pioglitazone, rosiglitazone or the
like improve insulin resistance by activating PPARγ to decrease
hypertrophic adipocytes by apoptosis, and promoting differentiation of
preadipocytes into small adipocytes having normal function (J. Biol.
Chem., 1995, vol. 270, p. 12953; J. Med. Chem., 1996, vol. 39, p. 665
etc.). Pioglitazone and rosiglitazone, which are PPARγ agonists,
have already been clinically used as therapeutic drugs for diabetes
(JP-A-61-267580, JP-A-1-131169 etc.).

[0003]PPARγ agonists are also useful as agents for treating and/or
preventing diseases besides diabetes, such as metabolic syndrome,
obesity, impaired glucose tolerance and other insulin resistance
syndrome, which are prediabetic conditions, hypertension,
atherosclerosis, hyperlipidemia, inflammatory diseases such as psoriasis
or the like, inflammatory bowel disease or the like.

[0004]On the other hand, angiotensin II receptors increase blood pressure
by constricting blood vessels via angiotensin II receptor type 1 on the
cellular membrane. Therefore, an angiotensin II receptor antagonist can
be an effective agent for treating and/or preventing of cardiovascular
diseases such as hypertension or the like (J. Med. Chem., 1996, vol. 39,
p. 625). Angiotensin II receptor antagonists such as losartan,
candesartan, telmisartan, valsartan, olmesartan or the like have already
been used clinically as antihypertensive agents (JP-A-4-364171,
JP-A-5-783228 etc.)

[0005]It is known that about 60% of hypertensive patients develop
complications of impaired glucose tolerance or type 2 diabetes (insulin
resistance). Despite the presence of various superior antihypertensive
agents, the blood pressure of such patients is poorly managed and
positive management of blood glucose is not practiced.

[0007]Meanwhile, a tricyclic compound represented by the following formula
(A) and a derivative thereof are known to have an excellent
antihypertensive action based on an angiotensin II receptor antagonistic
action (see patent references 6 and 9).

##STR00002##

[0008]In addition, a compound represented by the following formula (B) and
a derivative thereof are known as substances suppressing signal
transduction of GPR4 (see patent references 7 and 8).

[0010]Another object is to provide a novel tricyclic compound having a
PPARγ agonist activity or a pharmaceutically acceptable salt
thereof.

Means for Solving the Problems

[0011]The present invention relates to the following (1) to (47).

(1) An agent for activating PPARγ comprising, as an active
ingredient, a tricyclic compound represented by the formula (I)

##STR00004##

<wherein R1 represents lower alkyl optionally having
substituent(s), cycloalkyl optionally having substituent(s), lower alkoxy
optionally having substituent(s) or lower alkylsulfanyl optionally having
substituent(s), [0012]R2 and R3 are the same or different and
each represents a hydrogen atom, lower alkyl optionally having
substituent(s), lower alkenyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s), lower alkylcarbamoyl optionally having
substituent(s), di-lower alkylcarbamoyl optionally having substituent(s)
or aliphatic heterocyclecarbonyl optionally having substituent(s), or a
group

##STR00005##

[0012]in the formula (I) is selected from the group consisting of the
following formulas (a1) to (a20)

##STR00006## ##STR00007## ##STR00008##

[wherein R1 is as defined above, R6 and R7 are the same or
different and each represents a hydrogen atom, halogen, nitro, cyano,
formyl, oxo, hydroxy, lower alkoxy optionally having substituent(s),
lower alkanoyloxy optionally having substituent(s), lower alkyl
optionally having substituent(s), lower alkenyl optionally having
substituent(s), lower alkanoyl optionally having substituent(s), lower
alkoxycarbonyl optionally having substituent(s), --NR9R10
(wherein R9 and R10 are the same or different and each
represents a hydrogen atom, lower alkyl optionally having substituent(s),
lower alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s) or aralkyl optionally having
substituent(s), or R9 and R10 form, together with the adjacent
nitrogen atom thereto, a nitrogen-containing heterocyclic group
optionally having substituent(s)), --CONR11R12 (wherein
R11 and R12 are the same or different and each represents a
hydrogen atom, lower alkyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s) or aralkyl optionally having
substituent(s), or R11 and R12 form, together with the adjacent
nitrogen atom thereto, a nitrogen-containing heterocyclic group
optionally having substituent(s)), aryl optionally having substituent(s),
aralkyl optionally having substituent(s), an aromatic heterocyclic group
optionally having substituent(s) or an aliphatic heterocyclic group
optionally having substituent(s), and R8 represents a hydrogen atom
or lower alkyl optionally having substituent(s)], [0013]R4 and
R5 are the same or different and each represents a hydrogen atom,
halogen, hydroxy, lower alkoxy or lower alkyl, Q1-Q2-Q3
represents CH═CH--CH═CH, S--CH═CH or CH═CH--S, Y
represents a single bond, CH2, CH2CH2, CH═CH, O, S,
CH2O, OCH2, CH2S or SCH2,Z1-Z2 represents
C═CR13 (wherein R13 represents a hydrogen atom or lower
alkyl optionally having substituent(s)), CH--CR14R15 (wherein
R14 and R15 are the same or different and each represents a
hydrogen atom or lower alkyl optionally having substituent(s)), or
N--CR16R17 (wherein R16 and R17 are the same or
different and each represents a hydrogen atom or lower alkyl optionally
having substituent(s)), andA represents a group selected from the group
consisting of the following formulas (b1) to (b6)

##STR00009##

[0013](wherein R18 represents lower alkyl optionally having
substituent(s) or aryl optionally having substituent(s))>, or a
pharmaceutically acceptable salt thereof.(2) An agent having a
PPARγ agonistic action and an angiotensin II receptor antagonistic
action in combination, which comprises the tricyclic compound or the
pharmaceutically acceptable salt thereof recited in (1), as an active
ingredient.(3) The agent according to (1) or (2), wherein the agent is an
agent for treating and/or preventing a disease related to PPARγ.(4)
The agent according to (3), wherein the disease related to PPARγ is
a disease selected from the group consisting of type 2 diabetes, impaired
glucose tolerance, insulin resistance syndrome, hypertension,
hyperlipidemia, metabolic syndrome, visceral obesity, obesity and
hypertriglyceridemia.(5) A tricyclic compound represented by the formula
(IA)

##STR00010##

<wherein R1A represents lower alkyl optionally having
substituent(s), cycloalkyl optionally having substituent(s), lower alkoxy
optionally having substituent(s) or lower alkylsulfanyl optionally having
substituent(s), [0014]R2A and R3A are the same or different and
each represents a hydrogen atom, lower alkyl optionally having
substituent(s), lower alkenyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s), lower alkylcarbamoyl optionally having
substituent(s), di-lower alkylcarbamoyl optionally having substituent(s)
or aliphatic heterocycle-carbonyl optionally having substituent(s), or a
group

##STR00011##

[0014]in the formula (IA) is selected from the group consisting of the
following formulas (A1) to (A20)

##STR00012## ##STR00013## ##STR00014##

[wherein R1A is as defined above, R6A and R7A are the same
or different and each represents a hydrogen atom, halogen, nitro, cyano,
formyl, oxo, hydroxy, lower alkoxy optionally having substituent(s),
lower alkanoyloxy optionally having substituent(s), lower alkyl
optionally having substituent(s), lower alkenyl optionally having
substituent(s), lower alkanoyl optionally having substituent(s), lower
alkoxycarbonyl optionally having substituent(s), --NR9AR10A
(wherein R9A and R10A are the same or different and each
represents a hydrogen atom, lower alkyl optionally having substituent(s),
lower alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s) or aralkyl optionally having
substituent(s), or R9A and R10A form, together with the
adjacent nitrogen atom thereto, a nitrogen-containing heterocyclic group
optionally having substituent(s)), --CONR11AR12A (wherein
R11A and R12A are the same or different and each represents a
hydrogen atom, lower alkyl optionally having substituent(s), lower
alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s) or aralkyl optionally having
substituent(s), or R11A and R12A form, together with the
adjacent nitrogen atom thereto, a nitrogen-containing heterocyclic group
optionally having substituent(s)), aryl optionally having substituent(s),
aralkyl optionally having substituent(s), an aromatic heterocyclic group
optionally having substituent(s) or an aliphatic heterocyclic group
optionally having substituent(s), and R8A represents a hydrogen atom
or lower alkyl optionally having substituent(s)], R4A and R5A
are the same or different and each represents a hydrogen atom, halogen,
hydroxy, lower alkoxy or lower alkyl, Q1A-Q2A-Q3A
represents CH═CH--CH═CH, S--CH═CH or CH═CH--S, YA
represents a single bond, CH2, CH2CH2, CH═CH, O, S,
CH2O, OCH2, CH2S or SCH2,Z1A-Z2A represents
C═CR13A (wherein R13A represents a hydrogen atom or lower
alkyl optionally having substituent(s)), CH--CR14AR15A (wherein
R14A and R15A are the same or different and each represents a
hydrogen atom or lower alkyl optionally having substituent(s)), or
N--CR16AR17A (wherein R16A and R17A are the same or
different and each represents a hydrogen atom or lower alkyl optionally
having substituent(s)), and(i) when Z1A-Z2A is
C═CR13AA (wherein R13AA represents lower alkyl optionally
having substituent(s)), CH--CR14AR15AA (wherein R14A is as
defined above, and R15AA represents lower alkyl optionally having
substituent(s)), or N--CR16AAR17A (wherein R16AA is lower
alkyl optionally having substituent(s) and R17A is as defined
above),AA represents a group selected from the group consisting of
the following formulas (B1) to (B6)

##STR00015##

(wherein R18A represents lower alkyl optionally having substituent(s)
or aryl optionally having substituent(s)), and(ii) when Z1A-Z2A
is C═CR13AB (wherein R13AB represents a hydrogen atom),
CH--CR14ABR15AB (wherein both of R14AB and R15AB
represent a hydrogen atom), or N--CR16ABR17AB (wherein both of
R16AB and R17AB represent a hydrogen atom),AA represents a
group selected from the group consisting of the following formulas (B3)
to (B6)

##STR00016##

(wherein R18A is as defined above)>,or a pharmaceutically
acceptable salt thereof.(6) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to (5), wherein the
group

##STR00017##

in the formula (IA) is a group selected from the group consisting of the
aforementioned formulas (A1) to (A20).(7) The tricyclic compound or the
pharmaceutically acceptable salt thereof according to (5), wherein

##STR00018##

in the formula (IA) is a group selected from the group consisting of the
following formulas (A4), (A9), (A11) and (A12)

##STR00019##

(wherein R1A, R6A and R7A are as defined above,
respectively).(8) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to (5), wherein

##STR00020##

in the formula (IA) is a group represented by the following formula (A4)

##STR00021##

(wherein R1A, R6A and R7A are as defined above,
respectively).(9) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to (5), wherein

##STR00022##

in the formula (IA) is a group represented by the following formula (A12)

##STR00023##

(wherein R1A, R6A and R7A are as defined above,
respectively).(10) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to any of (5) to (9), wherein
Z1A-Z2A is C═CR13AA (wherein R13AA is as defined
above), CH--CHR15AA (wherein R15AA is as defined above), or
N--CR16AAR17A (wherein R16AA and R17A are as defined
above, respectively).(11) The tricyclic compound or the pharmaceutically
acceptable salt thereof according to any of (5) to (10), wherein AA is
the following formula (B3)

##STR00024##

(12) The tricyclic compound or the pharmaceutically acceptable salt
thereof according to any of (5) to (11), wherein
Q1A-Q2A-Q3A is CH═CH--CH═CH.(13) The tricyclic
compound or the pharmaceutically acceptable salt thereof according to any
of (5) to (12), wherein YA is CH2CH2 or CH2O.(14) A
pharmaceutical composition comprising the tricyclic compound or the
pharmaceutically acceptable salt thereof recited in any of (5) to (13) as
an active ingredient.(15) A PPARγ agonist comprising the tricyclic
compound or the pharmaceutically acceptable salt thereof recited in any
of (5) to (13) as an active ingredient.(16) An agent having a PPARγ
agonistic action and an angiotensin II receptor antagonistic action in
combination, which comprises the tricyclic compound or the
pharmaceutically acceptable salt thereof recited in any of (5) to (13) as
an active ingredient.(17) An agent for treating and/or preventing a
disease related to PPARγ, which comprises the tricyclic compound or
the pharmaceutically acceptable salt thereof recited in any of (5) to
(13) as an active ingredient.(18) The agent according to (17), wherein
the disease related to PPARγ is a disease further related to an
angiotensin II receptor.(19) The agent according to (17) or (18), wherein
the disease related to PPARγ is selected from the group consisting
of type 2 diabetes, impaired glucose tolerance, insulin resistance
syndrome, hypertension, hyperlipidemia, metabolic syndrome, visceral
obesity, obesity and hypertriglyceridemia.(20) An angiotensin II receptor
antagonist comprising the tricyclic compound or the pharmaceutically
acceptable salt thereof recited in any of (5) to (13) as an active
ingredient.(21) An agent for treating and/or preventing a disease related
to an angiotensin II receptor, which comprises the tricyclic compound or
the pharmaceutically acceptable salt thereof recited in any of (5) to
(13) as an active ingredient.(22) An antihypertensive agent which
comprises the tricyclic compound or the pharmaceutically acceptable salt
thereof recited in any of (5) to (13) as an active ingredient.(23) A
method of activating PPARγ, which comprises administering an
effective amount of the tricyclic compound or the pharmaceutically
acceptable salt thereof recited in (1).(24) A method of activating
PPARγ and antagonizing an angiotensin II receptor, which comprises
administering an effective amount of the tricyclic compound or the
pharmaceutically acceptable salt thereof recited in (1).(25) The method
according to (23) or (24), wherein the method of activating PPARγ
is a method for treating and/or preventing a disease related to
PPARγ.(26) The method according to (25), wherein the disease
related to PPARγ is a disease further related to an angiotensin II
receptor.(27) The method according to (25) or (26), wherein the disease
related to PPARγ is a disease selected from the group consisting of
type 2 diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity and hypertriglyceridemia.(28) A method of activating PPARγ,
which comprises administering an effective amount of the tricyclic
compound or the pharmaceutically acceptable salt thereof recited in any
of (5) to (13).(29) A method of activating PPARγ and antagonizing
an angiotensin II receptor, which comprises administering an effective
amount of the tricyclic compound or the pharmaceutically acceptable salt
thereof recited in any of (5) to (13).(30) The method according to (28)
or (29), wherein the method of activating PPARγ is a method for
treating and/or preventing a disease related to PPARγ.(31) The
method according to (30), wherein the treating the disease related to
PPARγ is a disease further related to an angiotensin II
receptor.(32) The method according to (30) or (31), wherein the disease
related to PPARγ is a disease selected from the group consisting of
type 2 diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity and hypertriglyceridemia.(33) A method of antagonizing an
angiotensin II receptor, which comprises administering an effective
amount of the tricyclic compound or the pharmaceutically acceptable salt
thereof recited in any of (5) to (13).(34) The method according to any of
(29) to (33), wherein the method of antagonizing an angiotensin II
receptor is a method for treating and/or preventing a disease related to
an angiotensin II receptor.(35) The method according to (34), wherein the
method for treating and/or preventing a disease related to an angiotensin
II receptor is a method for treating and/or preventing hypertension.(36)
Use of the tricyclic compound or the pharmaceutically acceptable salt
thereof recited in (1) for the production of a PPARγ agonist.(37)
Use of the tricyclic compound or the pharmaceutically acceptable salt
thereof recited in (1) for the production of an agent having a
PPARγ agonistic action and an angiotensin II receptor antagonistic
action in combination.(38) Use of the tricyclic compound or the
pharmaceutically acceptable salt thereof recited in (1) for the
production of an agent for treating and/or preventing a disease related
to PPARγ.(39) Use according to (38), wherein the disease related to
PPARγ is a disease selected from the group consisting of type 2
diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity and hypertriglyceridemia.(40) Use of the tricyclic compound or
the pharmaceutically acceptable salt thereof recited in any of (5) to
(13) for the production of a PPARγ agonist.(41) Use of the
tricyclic compound or the pharmaceutically acceptable salt thereof
recited in any of (5) to (13) for the production of an agent having a
PPARγ agonistic action and an angiotensin II receptor antagonistic
action in combination.(42) Use of the tricyclic compound or the
pharmaceutically acceptable salt thereof recited in any of (5) to (13)
for the production of an agent for treating and/or preventing a disease
related to PPARγ.(43) Use according to (42), wherein the disease
related to PPARγ is a disease further related to an angiotensin II
receptor.(44) Use according to (42) or (43), wherein the disease related
to PPARγ is a disease selected from the group consisting of type 2
diabetes, impaired glucose tolerance, insulin resistance syndrome,
hypertension, hyperlipidemia, metabolic syndrome, visceral obesity,
obesity and hypertriglyceridemia.(45) Use of the tricyclic compound or
the pharmaceutically acceptable salt thereof recited in any of (5) to
(13) for the production of an angiotensin II receptor antagonist.(46) Use
of the tricyclic compound or the pharmaceutically acceptable salt thereof
recited in any of (5) to (13) for the production of an agent for treating
and/or preventing a disease related to an angiotensin II receptor.(47)
Use of the tricyclic compound or the pharmaceutically acceptable salt
thereof recited in any of (5) to (13) for the production of an
antihypertensive agent.

[0020]Examples of the lower alkenyl include straight chain or branched
alkenyl having 2 to 10 carbon atoms, and more specific examples thereof
include vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl,
octenyl, nonenyl, decenyl and the like.

[0021]Examples of the cycloalkyl include cycloalkyl having 3 to 8 carbon
atoms, and more specific examples thereof include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the
like.

[0027]Halogen means each atom of fluorine, chlorine, bromine or iodine.

[0028]The substituent(s) of lower alkyl optionally having substituent(s),
lower alkenyl optionally having substituent(s), lower alkoxy optionally
having substituent(s), lower alkylsulfanyl optionally having
substituent(s), lower alkanoyloxy optionally having substituent(s), lower
alkanoyl optionally having substituent(s), lower alkoxycarbonyl
optionally having substituent(s), lower alkylcarbamoyl optionally having
substituent(s) and di-lower alkylcarbamoyl optionally having
substituent(s) are the same or different and examples thereof include 1
to 3 substituents selected from the group consisting of

[0030]The substituents of cycloalkyl optionally having substituent(s), an
aliphatic heterocyclic group optionally having substituent(s), aliphatic
heterocycle-carbonyl optionally having substituent(s) and a
nitrogen-containing heterocyclic group optionally having substituent(s),
which is formed together with the adjacent nitrogen atom thereto, are the
same or different and examples thereof include 1 to 3 substituents
selected from the group consisting of oxo, halogen, hydroxy, sulfanyl,
nitro, cyano, carbamoyl, C1-10 alkyl, trifluoromethyl, C3-8
cycloalkyl, C6-14 aryl, an aliphatic heterocyclic group, an aromatic
heterocyclic group,

[0031]Examples of C1-10 alkyl and the C1-10 alkyl moiety of
C1-10 alkoxy, C2-11 alkanoyloxy, C1-10 alkylsulfanyl,
C2-11 alkanoyl, C1-10 alkoxycarbonyl, C1-10 alkylcarbamoyl
and di-C1-10 alkylcarbamoyl shown here include the groups recited as
examples of the aforementioned lower alkyl. Two C1-10 alkyl in
di-C1-10 alkylcarbamoyl may be the same or different.

[0032]Examples of C3-8 cycloalkyl and the cycloalkyl moiety of
C3-8 cycloalkoxy include the groups recited as examples of the
aforementioned cycloalkyl.

[0033]Examples of C6-14 aryl and the aryl moiety of C6-14
aryloxy, C7-15 aroyl, C7-15 aroyloxy and C6-14
aryloxycarbonyl include the groups recited as examples of the
aforementioned aryl.

[0034]Examples of C7-16 aralkyl and the C7-16 aralkyl moiety of
C7-16 aralkyloxy and C7-16 aralkyloxycarbonyl include the
groups recited as examples of the aforementioned aralkyl.

[0035]Examples of the aliphatic heterocyclic group, the aromatic
heterocyclic group and halogen include the groups recited as examples of
the aforementioned aliphatic heterocyclic group, the aforementioned
aromatic heterocyclic group and the aforementioned halogen, respectively.

[0036]As compounds (1) and (IA), the compounds described in the
aforementioned (6) to (13) are more preferable. More specifically,
compounds represented by the formulas (IA-A) or (IA-B),

[0037]Still more preferably, in each of the groups of compounds (IA-A),
(IA-B), (IA-C), and (IA-D),

D is CH or N,

[0038]R1X is preferably, for example, methyl, ethyl, propyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy,
propoxy or the like, more preferably ethyl, propyl, cyclopropyl, ethoxy
or the like,R6X is preferably, for example, a hydrogen atom, a
fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl,
isopropyl or the like, more preferably a hydrogen atom, a chlorine atom,
methyl or the like, still more preferably a chlorine atom, methyl or the
like,R7X is preferably, for example, a hydrogen atom, a fluorine
atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl
or the like, more preferably a hydrogen atom, methyl or the like,YX
is more preferably, for example, CH2CH2, CH2O or the
like,R13X is preferably, for example, C1-6 alkyl or the like,
more preferably methyl, ethyl, propyl or the like, still more preferably
methyl or the like, andAX is preferably, for example, the
above-mentioned formula (b3).

[0040]The production methods of compound (I) are explained in the
following.

[0041]In the production methods shown below, when the defined groups
change under the conditions of the production methods or are
inappropriate for performing the production methods, the desired compound
can be produced by performing the methods for the introduction and
removal of the protecting groups conventionally performed in the
synthetic organic chemistry (e.g., methods described in Protective Groups
in Organic Synthesis, third edition, T. W. Greene, John Wiley & Sons
Inc., 1999 etc.) or the like. If necessary, the order of the reaction
steps such as substituent introduction or the like can also be changed.

Production Method 1

[0042]Of compound (I), a compound wherein A is the following formula (b1)
or (b2)

##STR00028##

can be produced by known methods (e.g., JP-B-2526005, JP-A-7-61983 and the
like), or similar methods thereto.

Production Method 2

[0043]Of compound (I), compounds (Ia) to (Id) wherein each of
Z1-Z2 is N--CR16R17 (wherein R16 and R17
are as defined above, respectively) and A is the following formula (b2),
(b3), (b4) or (b5)

##STR00029##

can be produced according to the following steps.

##STR00030##

[wherein R1, R2, R3, R4, R5, R16, R17,
Q1-Q2-Q3 and Y are as defined above, respectively, Xa
represents a leaving group such as a chlorine atom, a bromine atom, an
iodine atom, trifluoromethanesulfonyloxy, methanesulfonyloxy,
benzenesulfonyloxy, p-toluenesulfonyloxy or the like or a group
represented by the following formula

##STR00031##

(wherein X represents a chlorine atom, a bromine atom, an iodine atom,
trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy,
p-toluenesulfonyloxy or the like, Ra represents C1-10 alkyl,
C2-10 alkenyl, phenyl or benzyl, Rb and Rc are the same or
different and each represents C1-10 alkyl or C3-8 cycloalkyl,
or Rb and Rc form a nitrogen-containing heterocyclic group
together with the adjacent nitrogen atom thereto)].

Step 1

[0044]Compound (III) can be obtained by reacting compound (IIa) with 1
equivalent amount to 5 equivalent amount of compound (IIb) in a solvent
in the presence of, if necessary, 1 equivalent amount to large excess
amount of a base for 5 min to 120 hr at a temperature between -20°
C. and the boiling point of the solvent to be used.

[0046]Here, compound (IIa) can be obtained by the methods described in
JP-B-2526005, JP-A-7-61983 and the like, and compound (IIb) can be
obtained according to known methods (e.g., U.S. Pat. No. 5,332,744,
EP-B-400835, JP-A-5-783228 etc.) or similar methods thereto.

Step 2

[0047]Compound (IV) can be obtained by reacting compound (III) obtained in
step 1 with 1 equivalent amount to large excess amount of compound (IIIa)
and 1 equivalent amount to large excess amount of a cyanide salt in a
solvent or without solvent in the presence of 1 equivalent amount to
large excess amount of an acid for 5 min to 72 hr at a temperature
between -20° C. and the boiling point of the solvent to be used.

[0048]Examples of the cyanide salt include sodium cyanide, potassium
cyanide and the like. Examples of the acid include acetic acid,
trifluoroacetic acid and the like. Examples of the solvent include
dichloroethane, dioxane, THF, ethanol and the like, and these can be used
alone or in a mixture.

[0049]Here, compound (IIIa) can be obtained as a commercially available
product.

Step 3

[0050]Compound (Ia) can be obtained by reacting compound (IV) obtained in
step 2 with 1 equivalent amount to 10 equivalent amount of sodium azide
in a solvent in the presence of 1 equivalent amount to large excess
amount of a weak acid for 5 min to 120 hr at a temperature between
-20° C. and the boiling point of the solvent to be used.

[0051]Examples of the weak acid include ammonium chloride, triethylamine
hydrochloride and the like. Examples of the solvent include DMF, DMA,
NMP, DMSO and the like, and these can be used alone or in a mixture.

[0052]In addition, as another method, compound (Ia) can be also obtained
by reacting compound (IV) with 1 equivalent amount to 10 equivalent
amount of sodium azide in a solvent in the presence of 0.01 to 10
equivalent amount of an additive for 1 hr to 120 hr at a temperature
between -10° C. and the boiling point of the solvent to be used.

[0053]Examples of the additive include tributyltin chloride, trimethyltin
chloride, dibutyltin oxide and the like. Examples of the solvent include
toluene, xylene and the like, and these can be used alone or in a
mixture.

Step 4

[0054]Compound (Ib) can be produced using compound (IV) obtained in step 2
and according to the following steps.

[0055]Compound (Ib-1) can be obtained by reacting compound (IV) with 1
equivalent amount to large excess amount of hydroxylamine in a solvent
for 5 min to 120 hr at a temperature between -20° C. and the
boiling point of the solvent to be used.

[0056]As hydroxylamine, for example, an inorganic acid salt such as
hydroxylamine hydrochloride or the like can be used. In this case, it is
preferred that an equivalent amount of a base such as sodium methoxide or
the like coexist. Examples of the solvent include methanol, ethanol, DMF,
DMA, DMSO and the like, and these can be used alone or in a mixture.

Step 4-2

[0057]Compound (Ib-2) can be obtained by reacting compound (Ib-1) obtained
in the above-mentioned step 4-1 with 1 equivalent amount to large excess
amount of chlorocarbonate ester in a solvent in the presence of 1
equivalent amount to large excess amount of a base for 5 min to 72 hr at
a temperature between -20° C. and the boiling point of the solvent
to be used.

[0058]Examples of chlorocarbonate ester include methyl chlorocarbonate,
ethyl chlorocarbonate, propyl chlorocarbonate, phenyl chlorocarbonate and
the like. Examples of the base include triethylamine, pyridine,
4-dimethylaminopyridine (DMAP), sodium hydroxide, sodium hydride,
potassium tert-butoxide, sodium methoxide and the like. Examples of the
solvent include THF, DMF, DMA, toluene, xylene and the like, and these
can be used alone or in a mixture.

Step 4-3

[0059]Compound (Ib) can be obtained by reacting compound (Ib-2) obtained
in the above-mentioned step 4-2 in a solvent in the presence of, if
necessary, a catalytic amount to 10 equivalent amount of a base for 5 min
to 72 hr at a temperature between -20° C. and the boiling point of
the solvent to be used.

[0060]Examples of the base include sodium hydroxide, sodium hydride,
potassium tert-butoxide, sodium methoxide and the like. Examples of the
solvent include THF, DMF, DMA, toluene, xylene and the like, and these
can be used alone or in a mixture.

[0061]The above-mentioned steps 4-1 to 4-3 can also be performed
continuously by successively adding a reagent to the reaction mixture
without isolating the resultant product.

Step 5

[0062]Compound (Ic) can be obtained by reacting compound (Ib-1) obtained
from compound (IV) in the same manner as in the above-mentioned step 4-1,
with 1 equivalent amount to large excess amount of
N,N'-thiocarbonyldiimidazole in a solvent in the presence of 1 equivalent
amount to large excess amount of a base for 5 min to 72 hr at a
temperature between -20° C. and the boiling point of the solvent
to be used.

[0063]Examples of the base include triethylamine, pyridine, DMAP,
diazabicycloundecene (DBU) and the like. Examples of the solvent include
THF, 1,4-dioxane, dichloromethane, chloroform, acetonitrile, acetone and
the like, and these can be used alone or in a mixture.

Step 6

[0064]Compound (Id) can be obtained by reacting compound (Ib-1) obtained
from compound (IV) in the same manner as in the above-mentioned step 4-1,
with 1 equivalent amount to large excess amount of
N,N'-thiocarbonyldiimidazole in a solvent in the presence of 1 equivalent
amount to large excess amount of a Lewis acid for 5 min to 72 hr at a
temperature between -20° C. and the boiling point of the solvent
to be used.

[0065]Examples of Lewis acid include boron trifluoride diethyl ether
complex, stannous chloride, zinc chloride, silica gel and the like.
Examples of the solvent include THF, 1,4-dioxane, dichloromethane,
chloroform, methanol, ethanol and the like, and these can be used alone
or in a mixture.

Production Method 3

[0066]Compound (III) can also be produced according to the following
steps.

[0067]Compound (III) can be obtained by reacting compound (IIc) with 1
equivalent amount to 5 equivalent amount of compound (IIb) in a solvent
in the presence of 1 equivalent amount to large excess amount of a
condensation agent and, if necessary, 1 equivalent amount to large excess
amount of a phosphine compound for 5 min to 72 hr at a temperature
between -20° C. and the boiling point of the solvent to be used.

[0068]Examples of the condensation agent include diethyl azodicarboxylate,
diisopropyl azodicarboxylate, di(tert-butyl)azodicarboxylate,
(cyanomethylene)trimethylphosphorane, (cyanomethylene)tributylphosphorane
and the like. Examples of the phosphine compound include
triphenylphosphine, tributylphosphine, polymer supported
triphenylphosphine and the like. Examples of the solvent include THF,
DMF, dichloromethane, acetonitrile and the like, and these can be used
alone or in a mixture.

[0069]As another method, compound (III) can also be obtained by reacting
compound (IIc) in a solvent or without solvent in the presence of 1
equivalent amount to large excess amount of a halogenating agent for 5
min to 72 hr at a temperature between -20° C. and the boiling
point of the solvent to be used, and successively in the same manner as
in step 1 of production method 2.

[0070]Examples of the halogenating agent include thionyl chloride;
phosphorus tribromide; a combination of triphenylphosphine, 2,6-lutidine
and carbon tetrachloride; a combination of triphenylphosphine,
2,6-lutidine and carbon tetrabromide; a combination of methanesulfonyl
chloride and lithium chloride, a combination of methanesulfonyl chloride
and lithium bromide and the like. Examples of the solvent include THF,
DMF, DMA, dichloromethane, dichloroethane, acetonitrile and the like, and
these can be used alone or in a mixture.

and Z1-Z2 is C═CR13 (wherein R13 is as defined
above), can be produced according to the following steps.

##STR00035##

(wherein Xc is as Xa defined above or hydroxy, R1, R2,
R3, R4, R5, R13, Q1-Q2-Q3 and Y are as
defined above, respectively and A1 represents a group represented by
any of the above-mentioned formulas (b1) to (b5)).

Step 8

[0073]Compound (VI) can be obtained by using compound (V) and compound
(IIb) and in the same manner as in the known methods described in
production method 1, step 1 of production method 2 or production method
3.

[0074]Here, compound (V) can be obtained according the method described in
JP-B-2526005 and the like.

Step 9

[0075]Compound (Ie) can be obtained by using compound (VI) obtained in
step 8 and in the same manner as in the known method described in
production method 1 or steps 3 to 6 of production method 2.

Production Method 5

[0076]Of compound (I), compound (If) wherein Z1-Z2 is
CH--CR14R15 (wherein R14 and R15 are as defined
above, respectively) can be obtained according to the following steps.

[0077]Compound (VIII) can be obtained by using compound (VII) and compound
(IIb) and in the same manner as in the known methods described in
production method 1, step 1 of production method 2 or production method
3.

[0078]Here, compound (VII) can be obtained according to the method
described in JP-B-2526005 and the like.

Step 11

[0079]Compound (If) can be obtained by using compound (VIII) obtained in
step 10 and in the same manner as in the known methods described in
production method 1 or steps 3 to 6 of production method 2.

Production Method 6

[0080]Of compound (I), compound (Ih) wherein A is

##STR00037##

(wherein R18 is as defined above), can be obtained according to the
following step.

[0081]Compound (Ih) can be obtained by treating compound (Ig) obtained in
production method 1 with 1 to 50 equivalent amount of a carboxylic acid
activator, and then, by reacting the compound with 1 to 50 equivalent
amount of compound (VII) in a solvent in the presence of 1 to 30
equivalent amount of a base for 5 min to 72 hr at a temperature between
-20° C. and the boiling point of the solvent to be used.

[0082]Examples of the carboxylic acid activator include
N,N'-carbonyldiimidazole (CDI),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) or hydrochloride
thereof, dicyclohexylcarbodiimide (DCC) and the like. Examples of the
solvent include dichloromethane, acetonitrile, toluene, ethyl acetate,
THF, 1,4-dioxane, DMF, NMP and the like, and these can be used alone or
in a mixture. Examples of the base include DBU, triethylamine, DMAP,
N,N-dimethylaniline, pyridine, N-methylmorpholine and the like. In
addition, compound (VII) can be obtained as a commercially available
product.

[0083]The functional groups contained in R1, R2, R3,
R4, R5, Z1, Z2, A, and Y in compound (I) can also be
converted by a known method (e.g., the method described in Comprehensive
Organic Transformations 2nd edition, R. C. Larock, Vch
Verlagsgesellschaft Mbh, 1999 and the like) or similar methods thereto.

[0084]The intermediates and the desired compounds in the above-mentioned
respective production methods can be isolated and purified by applying
separation purification methods usually used in the synthetic organic
chemistry such as filtration, extraction, washing, drying, concentration,
recrystallization, various chromatographies or the like. In addition,
intermediates can also be subjected to a next reaction without particular
purification.

[0085]Some of compounds (1) and (IA) contain a geometric isomer, a
stereoisomer such as an optical isomer and the like, a tautomer and the
like. The present invention comprises all possible isomers and mixtures
thereof including these.

[0086]When a salt of compound (I) or (IA) is to be obtained, compound (I)
or (IA) obtained in the form of a salt can be directly purified. When it
is obtained in a free form, compound (I) or (IA) may be dissolved or
suspended in a suitable solvent, and an acid or base is added thereto to
form a salt, which may be isolated and purified.

[0087]While compounds (I) and (IA) and pharmaceutically acceptable salts
thereof may exist in the form of adducts with water or various solvents,
these adducts are also comprised in the present invention.

[0088]Specific examples of compound (I) obtained by the present invention
are shown in Table 1 to Table 34. However, the compound of the present
invention is not limited to them.

[0090]Next, the pharmacological action of the representative compound (I)
is specifically explained by Test Examples.

Test Example 1

Examination of PPARγ Activation Action Based on Transactivation
Assay of PPARγ by Transient Gene Transfer

[0091]The agonist activity of compound (I) to PPARγ was determined
by a transactivation assay method using a chimeric nuclear receptor of a
DNA binding region of a yeast transcription factor GAL4 and a PPARγ
ligand binding region. Specifically, the PPARγ agonist activity of
compound (I) was evaluated by the following method based on the method of
Lehmann et al. (J Biol. Chem., 1995, vol. 270, page 12953).

[0092]HEK293EBNA cells cultured in Dulbecco's Modified Eagle medium
(Invitrogen) containing 10 v/v % fetal calf serum (Invitrogen) were used.
30 mL of the above-mentioned cells (density: 1×105 cells/mL)
were inoculated in a 10 cm2 culture dish (Iwaki Glass), and cultured
overnight. Using SuperFect Transfection Reagent (QIAGEN), a plasmid
expressing a GAL4-PPARγ chimeric nuclear receptor fusing 174-475
amino acids, which are human PPARγ ligand binding region, and 1-147
amino acids, which are GAL4 DNA binding region, and a reporter plasmid
expressing a GAL4 responsive luciferase were transiently introduced into
the cells at a proportion of 4:1. After 5 hr from gene introduction, the
cells were detached from the culture dish, and the detached cells
(density: 2×104 cells/mL) were inoculated by 100 μL in each
well of a 96 well white plate (SUMITOMO BAKELITE), and cultured
overnight. The medium was removed, compound (I) diluted in various
concentrations with serum-free Dulbecco's Modified Eagle medium was added
by 100 μL, and the mixture was reacted under a 5% carbon dioxide gas
stream (5% CO2) at 37° C. for 24 hr. On the other hand, as a
positive control, 10 μmol/L of pioglitazone (100 μL) was added, and
the mixture was reacted under a 5% carbon dioxide gas stream (5%
CO2) at 37° C. for 24 hr. As a substrate of luciferase, 100
μL of Steady-Glo (Promega) was added to each well and the mixture was
thoroughly stirred. Immediately thereafter, the chemical luminescence due
to luciferase was measured using TopCount NTX (Packard).

[0093]The agonist activity (activity rate (%)) of compound (I) to
PPARγ was calculated according to the following formula, as a
relative activity when the agonist activity on addition of pioglitazone
(10 μmol/L) was 100%.

[0094]The activity rate at which compound (I) shows the maximum activity
is referred as efficacy and the concentration showing 50% activity rate
of the efficacy was calculated as EC50 value. The results are shown
in Table 35.

[0101]Compound (I) was orally administered to db/db mouse (7-week-old,
female), a model of spontaneous type 2 diabetes, at a dose of 30
mg/kg/day once a day for 6 days. A solvent (0.5% methylcellulose
solution) was administered to the control group. After 7 days from the
administration, glucose and triglyceride in plasma were measured.
Statistically significant difference was examined using Student's t test,
and risk rate (P)<0.05 was taken as significant.

[0102]As a result, compound (I) remarkably suppressed an increase of serum
glucose and triglyceride, and compound (I) was confirmed to have a
glucose- and lipid-lowering actions in the diabetes model in this
Experiment.

[0103]A test compound was repeatedly administered orally to Zucker obese
rat, a model of type 2 diabetes, once a day for 4 weeks at a dose of 3
mg/kg. A solvent (0.5% methylcellulose solution) was administered to the
control group in a similar manner. After 4 weeks of administration, an
oral glucose tolerance test was performed as shown below. In addition,
plasma insulin level was measured under full feeding condition.

[0104]Oral glucose tolerance test: After rat was fasted overnight, a
glucose solution was orally administered at a dose of 2 g/kg. Blood
samples were collected from the rat tail vein at 30 min, 60 min and 120
min after administration of the glucose solution, and the blood glucose
level was measured.

[0105]Some of the compound (I) of the present invention were evaluated as
the above-mentioned test compounds. These compounds showed improving
actions of impaired glucose tolerance and insulin resistance. It could
also be confirmed that they improved obesity.

[0107]Before drug administration, the body weight, blood pressure and
heart rate of each rat were measured, and the rats were grouped such that
these values are almost the same between groups. A solvent (0.5%
methylcellulose solution) and a test compound were repeatedly
administered orally once a day for 7 days. At about 4 to 9 hr after the
final administration, systolic blood pressure and heart rate were
non-invasively measured according to the following.

[0108]Measurement methods of blood pressure and heart rate

[0109]The rats were placed in a cylindrical restrainer, heated to
37° C., and blood pressure and heart rate were measured under
resting state using a Tail Cuff Method. For the measurement, a
non-invasive blood pressure measurement apparatus (PS-600, Riken
Kaihatsu, Tokyo) was used. The blood pressure and heart rate of each rat
was measured 5 times, and the average was taken as the value of each rat.

[0110]As the results of the above-mentioned test, compounds 26, 29, 42,
44, 47, S13, 95, 137, 139 and the like were confirmed to have
antihypertensive action.

Test Example 6

Examination of Antihypertensive Action of Compound (I) by Telemetry Method

[0111]A telemetry transmitter was indwelled in the abdominal artery of
spontaneously hypertensive rats (SHR), and the blood pressure and heart
rate were monitored. The rats were acclimated and reared for 4 weeks or
more, and only the rats with hypertension were used for the test. Before
drug administration, the rats were grouped such that the blood pressure
and heart rate of each rat would be of the same levels between the
groups. A solvent (0.5% methylcellulose solution) and a test compound
were repeatedly administered orally once a day for 4 days. The average
systolic blood pressure for 24 hr, average diastolic blood pressure for
24 hr and average heart rate for 24 hr were calculated on each
administration day.

[0114]It is known that about 60% of hypertension patients develops
complications of impaired glucose tolerance or type 2 diabetes (insulin
resistance). Accordingly, compound (I) or (IA) or a pharmaceutically
acceptable salt thereof of the present invention is specifically expected
as an agent for treating and/or preventing hypertension that concurrently
developed impaired glucose tolerance or type 2 diabetes (insulin
resistance), and as an agent for treating and/or preventing hypertension,
which has a prophylactic effect on impaired glucose tolerance or type 2
diabetes (insulin resistance).

[0115]While compounds (1) or (IA) or pharmaceutically acceptable salts
thereof can be administered alone as they are, generally, they are
desirably provided as various pharmaceutical preparations. In addition,
such pharmaceutical preparations are used for animals and humans.

[0116]The pharmaceutical preparation relating to the present invention can
contain, as an active ingredient, compound (I) or (IA) or a
pharmaceutically acceptable salt thereof alone or as a mixture with an
active ingredient for any other treatment. Moreover, the pharmaceutical
preparation can be produced by mixing the active ingredient with one or
more kinds of pharmaceutically acceptable carriers (e.g., diluent,
solvent, excipient or the like) according to any method well known in the
technical field of galenical pharmacy.

[0117]As the administration route, a route most effective for the
treatment is desirably employed, which may be an oral or parenteral route
such as intravenous route or the like.

[0118]The dosage form may be, for example, tablet, injection or the like.

[0119]A form suitable for oral administration, such as tablet or the like,
can be produced by using an excipient such as lactose or the like, a
disintegrant such as starch or the like, a lubricant such as magnesium
stearate or the like, a binder such as hydroxypropylcellulose or the
like.

[0120]A form suitable for parenteral administration, such as injection or
the like, can be produced by using a diluent such as a salt solution, a
glucose solution or a mixture of salt solution and a glucose solution or
the like, or a solvent or the like.

[0121]While the dose and administration frequency of compound (1) or (IA)
or a pharmaceutically acceptable salt thereof varies depending on the
mode of administration, age and body weight of patients, nature and
severity of the symptom to be treated or the like, it is generally within
the range of 0.01 to 1000 mg, preferably 0.05 to 100 mg, for oral
administration to an adult, which is administered at once or in several
portions a day. In the case of parenteral administration such as
intravenous administration or the like, 0.001 to 1000 mg, preferably 0.01
to 100 mg, is administered to an adult at once or in several portions a
day. However, these doses and administration frequencies vary depending
on the aforementioned various conditions.

[0122]The PPARγ agonist of the present invention shows an excellent
treatment and/or preventive effect on a disease related to PPARγ
(e.g., type 2 diabetes, impaired glucose tolerance, insulin resistance
syndrome, hypertension, hyperlipidemia, metabolic syndrome, visceral
obesity, obesity, hyperglyceridemia etc.). As mentioned above, compound
(I) or a pharmaceutically acceptable salt thereof can also be used in
combination with one or more kinds of other pharmaceutical components.

[0124]When compound (I) or a pharmaceutically acceptable salt thereof and
other pharmaceutical component are used in combination, compound (I) or a
pharmaceutically acceptable salt thereof and other pharmaceutical
component may be simultaneously administered or separately in a staggered
manner. The dose thereof only need to follow clinically employed doses,
which varies depending on the administration subject, administration
route, disease, combination of pharmaceutical components or the like.

[0125]The present invention is explained in more detail in the following
by Examples and Reference Examples, which are not to be construed as
limitative.

[0126]The proton nuclear magnetic resonance spectrum (1H NMR) used in
the Examples and Reference Examples were measured at 270 MHz or 300 MHz,
and exchanging protons may not be clearly observed depending on the
compound and measurement conditions. The indication of the multiplicity
of the signals is conventional, where br means an apparently broad
signal.

Reference Example 1

2-ethyl-4,6-dimethylbenzimidazole

[0127]To a mixture of 2,4-dimethylaniline (0.918 mL, 7.42 mmol) and
propionic anhydride (6.0 mL) fuming nitric acid (1.25 mL, 29.7 mmol) was
added dropwise under ice-cooling over 20 min. Under ice-cooling, the
mixture was stirred for 1 hr and added with water and ethyl acetate,
followed by extraction. The organic layer was washed with saturated
aqueous sodium hydrogen carbonate solution and brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure.
Ethyl acetate-hexane (1/1, 24 mL) was added to the residue, and the
precipitated solid was collected by filtration. The obtained solid was
dissolved in methanol (17 mL), and the mixture was stirred in the
presence of 10% palladium carbon (448 mg) under a hydrogen atmosphere at
room temperature for 1 hr. The mixture was filtrated, and the filtrate
was concentrated under reduced pressure. The residue was dissolved in
acetic acid (14 mL) and the mixture was stirred at 110° C. for 30
min. The mixture was concentrated under reduced pressure, diluted with
chloroform, and washed with saturated aqueous sodium hydrogen carbonate
solution and brine. The organic layer was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. Ethyl acetate-hexane
(1/5, 30 mL) was added to the residue, and the precipitated solid was
collected by filtration to give the title compound (585 mg, 45%).

[0139][step 2] To a solution of sodium hydride (60%, 0.856 g, 21.4 mmol)
and diethyl 1-cyanoethylphosphonate (4.09 g, 21.4 mmol) in DMF (35 mL), a
solution of ethyl
10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylate (3.0 g,
10.7 mmol) obtained in step 1 in DMF (10 mL) was added under ice-cooling,
and the mixture was stirred at 80° C. for 3 hr. Water was added to
the mixture, and the mixture was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give a residue. The obtained
residue was dissolved in THF (50 mL), followed by adding lithium
borohydride (1.11 g, 50.9 mmol) and the mixture was stirred at 50°
C. for 5 hr. The mixture was neutralized with 2 mol/L hydrochloric acid,
and extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(chloroform/ethyl acetate=98/2) to give
(E)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene-
)propiononitrile (0.730 g, 27%) and
(Z)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene-
)propiononitrile (0.728 g, 27%), respectively.

[0142]5-Cyanomethyl-2-[5-ethoxycarbonyl-4-(1-hydroxy-1-methyl)ethyl-2-prop-
ylimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (2.21 g, 4.5
mmol) obtained in step 2 of Example 10, was dissolved in DMF (23 mL), and
the solution was added with sodium azide (1.18 g, 18.2 mmol) and
triethylamine hydrochloride (1.87 g, 13.6 mmol), followed by stirring at
90° C. for 20 hr. A 5% aqueous citric acid solution was added to
the mixture, and the mixture was extracted with chloroform. The organic
layer was washed with brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (chloroform/methanol=25/1) to give the title
compound (compound S7, 1.97 g, 81.9%).

[0154][step 2]
2-[5-Ethoxycarbonyl-4-(1-hydroxy-1-methyl)ethyl-2-propylimidazol-1-yl]met-
hyl-5-(2-trityl-2H-tetrazol-5-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepi-
ne (979 mg, 1.27 mmol) obtained in step 1 was dissolved in a mixed solvent
of THF-methanol-water (12 mL-3 mL-3 mL), and the solution was added with
lithium hydroxide monohydrate (266 mg, 6.34 mmol), followed by stirring
at room temperature for 15 min. The mixture was concentrated under
reduced pressure. Chloroform and brine were added to the residue, and the
mixture was neutralized with 1 mol/L hydrochloric acid and extracted with
chloroform. The organic layer was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure to give
2-[5-carboxy-4-(1-hydroxy-1-methyl)ethyl-2-propylimidazol-1-yl]methyl-5-(-
2-trityl-2H-tetrazol-5-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine
(1.15 g) quantitatively.

[0171]2,3-Diaminopyridine (7.84 g, 71.9 mmol) and tetraethoxymethane (35
mL, 167 mmol) were mixed, and the mixture was stirred at 130° C.
for 2 hr. The mixture was cooled to room temperature, ethyl acetate (100
mL) was added thereto and the precipitated solid was collected by
filtration to give the title compound (4.17 g, 36%).

[0173]2-Ethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 4.00 g,
27.2 mmol) was dissolved in chloroform (45 mL), and the solution was
added with m-chloroperbenzoic acid (5.18 g, 29.9 mmol) followed by
stirring at room temperature for 5 hr. The reaction mixture was
concentrated, added with ethyl acetate and water, and partitioned between
ethyl acetate and water. The aqueous layer was concentrated and the
residue was dissolved in chloroform (8 mL). Phosphorus oxychloride (24
mL, 257 mmol) was added thereto and the mixture was stirred at room
temperature for 2 hr. The reaction mixture was poured onto ice,
neutralized with aqueous ammonia, and extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. Ethyl acetate (30 mL)
was added to the residue and the precipitated solid was collected by
filtration to give the title compound (3.32 g, 67%).

[0177]The title compound (3.22 g, 55%) was obtained in the same manner as
in Reference Example 22, using 2-cyclopropyl-3H-imidazo[4,5-b]pyridine
(EP420237; 4.79 g, 30.1 mmol) instead of
2-ethyl-3H-imidazo[4,5-b]pyridine.

[0181]2-Chloro-6-nitroaniline (3.00 g, 17.4 mmol) and pyridine (7.0 mL,
86.9 mmol) were dissolved in DMA (17 mL), and the solution was added with
cyclopropanecarbonylchloride (4.0 mL, 43.5), followed by stirring at
50° C. for 3 hr. Methanol (10 mL) and aqueous ammonia (9 mL) were
added to the reaction mixture, and the mixture was stirred at room
temperature for 30 min. Water (10 mL) was added, and the precipitated
solid was collected by filtration. The solid was suspended in ethanol (38
mL) and water (38 mL) and the solution was added with ferrous sulfate 7
hydrate (13.86 g, 49.9 mmol) and aqueous ammonia (19 mL), followed by
stirring at 50° C. for 4 hr. The reaction mixture was filtrated,
and the filtrate was extracted with ethyl acetate, washed with brine,
dried over anhydrous magnesium sulfate, and concentrated under reduced
pressure. Acetic acid (8 mL) was added to the residue, and the mixture
was stirred at 90° C. for 1 hr. The reaction mixture was
concentrated under reduced pressure, and the residue was neutralized with
aqueous sodium hydroxide solution, and the mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure.
Ethyl acetate (5 mL) and diisopropyl ether (5 mL) were added to the
residue and the precipitated solid was collected by filtration to give
the title compound (1.20 g, 36%).

[0187][step 1] Propionic anhydride (40 mL) was cooled to 0° C.,
added with 2-chloroaniline (5.0 mL, 47.5 mmol) and the mixture was
stirred for 15 min. While maintaining the inside temperature at
10° C. or below, fuming nitric acid (8.0 mL, 190 mmol) was added
dropwise, and the mixture was stirred under ice-cooling for 15 min. Water
(100 mL) was added to the reaction mixture, and the precipitated solid
was collected by filtration. The solid was dried and recrystallized from
ethyl acetate (50 mL) to give N-(2-chloro-6-nitrophenyl)propionamide
(3.73 g, 34%).

[0194][step 2] Methyl
(E)-11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepine-3-carboxylate
(6.40 g, 21.0 mmol) was suspended in THF (105 mL), and the solution was
added with lithium borohydride (2.29 g, 105 mmol), followed by stirring
at 50° C. for 6 hr. Ice was added to the reaction mixture, and the
mixture was neutralized with 1 mol/L hydrochloric acid to pH 2, and
extracted twice with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:hexane=30:70) to give the title compound
(4.89 g, 17.6 mmol, 84.1%).

[0199][step 1] 2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat.
No. 5,332,744; 36.55 g, 209 mmol) was dissolved in DMF (365.5 mL), and
the solution was added with lithium hydroxide (5.62 g, 235 mmol),
followed by stirring at room temperature for 15 min.
1-(10,11-Dihydro-5H-dibenzo[b,f]azepin-2-ylmethyl)-1-methylpiperidinium
iodide (JP-A-7-61983; 95.0 g, 219 mmol) and DMF (73.1 mL) were added
thereto, and the mixture was stirred at 40° C. for 8 hr. After
cooling to room temperature, water (175.4 mL) was added dropwise, and the
mixture was stirred under ice-cooling for 2 hr. The precipitate was
collected by filtration, and dissolved in chloroform (520 mL) with
heating. Activated carbon (5.2 g) was added, and the mixture was stirred
for 30 min with heating, and the hot solution was filtered. Ethyl acetate
(1041 mL) was added to the filtrate, and the precipitate was collected by
filtration to give
2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydr-
o-5H-dibenzo[b,f]azepine (36.7 g, 46%).

[0203][step 3]
5-Cyanomethyl-2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methy-
l-10,11-dihydro-5H-dibenzo[b,f]azepine (200 mg, 0.47 mmol) obtained in
step 2 was dissolved in ethanol (4 mL), and the solution was added with
hydroxylamine (50% aqueous solution, 0.15 mL, 2.37 mmol), followed by
heating under reflux for 1 hr. The mixture was concentrated under reduced
pressure. The obtained residue was dissolved in DMF (1 mL) and the
solution was added with pyridine (46 μL, 0.57 mmol) and ethyl
chlorocarbonate (54 μL, 0.57 mmol) at 0° C., followed by
stirring at room temperature for 2 hr. Ethyl acetate and saturated
aqueous sodium hydrogen carbonate solution were added thereto. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The obtained residue
was dissolved in toluene (10 mL), and the solution was added with
potassium tert-butoxide (51 mg, 0.45 mmol), followed by stirring at room
temperature for 15 min. Ethyl acetate was added to the mixture, and the
organic layer was washed with 5% aqueous citric acid solution, dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure to
give the title compound (compound 1, 190 mg, 83%).

[0209][step 3] The title compound (compound 2, 69 mg, 32%) was obtained in
the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimida-
zol-1-yl]methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (0.20 g, 0.36 mmol)
obtained in step 2.

[0215][step 3] The title compound (compound 3, 173 mg, 70%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)meth-
yl-10,11-dihydro-5H-dibenzo[b,f]azepine (218 mg, 0.501 mmol) obtained in
step 2.

[0221][step 3] The title compound (compound 4, 28.2 mg, 46%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2,5-diethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methy-
l-10,11-dihydro-5H-dibenzo[b,f]azepine (54.0 mg, 0.124 mmol) obtained in
step 2.

[0227][step 3] The title compound (compound 5, 71.5 mg, 51%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-ethyl-4,6-dimethylbenzimidazol-1-yl)methyl-10,11-dihyd-
ro-5H-dibenzo[b,f]azepine (122 mg, 0.290 mmol) obtained in step 2.

[0233][step 3] The title compound (compound 6, 0.20 g, 35%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro--
5H-dibenzo[b,f]azepine (0.50 g, 1.19 mmol) obtained in step 2.

[0239][step 3] The title compound (compound 7, 119 mg, 66%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)meth-
yl-10,11-dihydro-5H-dibenzo[b,f]azepine (159 mg, 0.363 mmol) obtained in
step 2.

[0245][step 3] The title compound (compound 8, 69.0 mg, 60%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-methoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)met-
hyl-10,11-dihydro-5H-dibenzo[b,f]azepine (101 mg, 0.238 mmol) obtained in
step 2.

[0251][step 3] The title compound (compound 9, 20.6 mg, 23%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10-
,11-dihydro-5H-dibenzo[b,f]azepine (79.0 mg, 0.194 mmol) obtained in step
2.

[0257][step 3] The title compound (compound 10, 106 mg, 72%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-[5-ethoxycarbonyl-4-(1-hydroxy-1-methyl)ethyl-2-propylimi-
dazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (131 mg, 0.269
mmol) obtained in step 2.

[0263][step 3] The title compound (compound 11, 97.5 mg, 69%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-[5-ethoxycarbonyl-2-ethyl-4-(1-hydroxy-1-methyl)ethylimid-
azol-1-yl]methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (126 mg, 0.267 mmol)
obtained in step 2.

[0269][step 3] The title compound (compound 12, 92.4 mg, 81%) was obtained
in the same manner as in step 3 of Example 1, using
2-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-cyano-
methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (101 mg, 0229 mmol) obtained
in step 2.

[0275][step 3] The title compound (compound 13, 195 mg, 77%) was obtained
in the same manner as in step 3 of Example 1, using
2-(2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-cyanomethy-
l-10,11-dihydro-5H-dibenzo[b,f]azepine (225 mg, 0.500 mmol) obtained in
step 2.

[0281][step 3] The title compound (compound 14, 163 mg, 60%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(5-ethoxycarbonyl-4-ethyl-2-propylimidazol-1-yl)methyl-10-
,11-dihydro-5H-dibenzo[b,f]azepine (242 mg, 0.530 mmol) obtained in step
2.

[0287][step 3] The title compound (compound 15, 65.3 mg, 87%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyri-
din-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (66.6 mg, 0.140 mmol)
obtained in step 2.

[0293][step 3] The title compound (compound 16, 48.1 mg, 84%) was obtained
in the same manner as in step 3 of Example 1, using
2-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-cyano-
methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (50.7 mg, 0.115 mmol) obtained
in step 2.

[0299][step 3] The title compound (compound 17, 118 mg, 64%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(7-fluoro-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-
-dihydro-5H-dibenzo[b,f]azepine (162 mg, 0.369 mmol) obtained in step 2.

[0307][step 2] The title compound (compound 19, 114 mg, 30%) was obtained
in the same manner as in step 3 of Example 1, using
5-(1-cyanoethyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)me-
thyl-10,11-dihydro-5H-dibenzo[b,f]azepine (337 mg, 0.774 mmol) obtained in
step 1.

[0311][step 2] The title compound (compound 20, 98 mg, 46%) was obtained
in the same manner as in step 3 of Example 1, using
5-(1-cyanoethyl)-2-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-
-10,11-dihydro-5H-dibenzo[b,f]azepine (186 mg, 0.44 mmol) obtained in step
1.

[0315][step 2] The title compound (compound 21, 255 mg, 41%) was obtained
in the same manner as in step 3 of Example 1, using
2-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-5-(1-cy-
anoethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (550 mg, 1.2 mmol) obtained
in step 1.

[0321][step 2] The title compound (compound 23, 265 mg, 36%) was obtained
in the same manner as in Example 22, using
5-(1-cyanopropyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)m-
ethyl-10,11-dihydro-5H-dibenzo[b,f]azepine (671 mg, 1.49 mmol) obtained in
step 1.

[0325][step 2] The title compound (compound 24, 101 mg, 13%) was obtained
in the same manner as in Example 22, using
5-(1-cyanobutyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)me-
thyl-10,11-dihydro-5H-dibenzo[b,f]azepine (695 mg, 1.50 mmol) obtained in
step 1.

[0335][step 3] The title compound (compound 27, 956 mg, 70%) was obtained
in the same manner as in Example 22, using
5-(1-cyanoethyl)-2-(7-methyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methy-
l-10,11-dihydro-5H-dibenzo[b,f]azepine (1.31 g, 2.9 mmol) obtained in step
2.

[0339][step 2] The title compound (compound S7, 200 mg, 38%) was obtained
in the same manner as in Example 22, using
5-(1-cyanoethyl)-2-(5-ethoxycarbonyl-4-ethyl-2-propyl-1H-imidazol-1-yl)me-
thyl-10,11-dihydro-5H-dibenzo[b,f]azepine (480 mg, 1.0 mmol) obtained in
step 2.

[0341][step 1]
(E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile (JP-B-2526005; 1.26 g, 4.8 mmol) was dissolved in THF (50 mL),
and the solution was added with 2,6-lutidine (3.4 mL, 29.2 mmol), lithium
bromide (2.54 g, 29.2 mmol) and methanesulfonic anhydride (2.02 g, 11.6
mmol), followed by stirring at room temperature for 24 hr. Ethyl acetate
was added to the mixture, and the organic layer was washed with brine.
The organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give a residue.

[0342]2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.85 g, 4.8 mmol)
was dissolved in DMF (15 mL), and the solution was added with potassium
tert-butoxide (0.60 g, 5.3 mmol) at 0° C. followed by stirring for
10 min. Thereto was added a solution of the residue obtained above in DMF
(8 mL), and the mixture was stirred at room temperature for 2 hr. Ethyl
acetate was added to the mixture, the organic layer was washed with
brine, dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=3/1-1/3) to give
(E)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (1.28 g, 63%).

[0344][step 2] The title compound (compound 29, 215 mg, 75%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (250 mg, 0.60
mmol) obtained in step 1.

[0348][step 2] The title compound (compound 30, 0.27 g, 35%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-[2-(6-methoxycarbonyl-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-
-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (0.68 g, 1.43
mmol) obtained in step 1.

[0352][step 2] The title compound (compound 31, 0.31 g, 66%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (0.42 g, 0.96
mmol) obtained in step 1.

[0356][step 2] The title compound (compound 32, 0.20 g, 88%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]m-
ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
(0.20 g, 0.37 mmol) obtained in step 1.

[0360][step 2] The title compound (compound 33, 0.20 g, 45%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo-
[a,d]cyclohepten-5-ylidene]acetonitrile (0.40 g, 0.96 mmol) obtained in
step 1.

[0365][step 2] The title compound (compound 34, 102 mg, 44%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-[2-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihyd-
ro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (200 mg, 0.49 mmol)
obtained in step 1.

[0369][step 2] The title compound (compound 35, 80 mg, 49%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-{2-[5-ethoxycarbonyl-4-(1-hydroxy-1-methyl)ethyl-2-propylimidazol-1-y-
l]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile
(144 mg, 0.3 mmol) obtained in step 1.

[0373][step 2] The title compound (compound 36, 54 mg, 52%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-[2-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10-
,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (90 mg, 0.21
mmol) obtained in step 1.

[0377][step 2] The title compound (compound 37, 184 mg, 76%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-[2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridin-3-yl)-
methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
(221 mg, 0.47 mmol) obtained in step 1.

[0379][step 1]
(E)-[2-(5-Methyl-2-propyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridin-3-yl-
)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
was obtained as a crude product in the same manner as in step 1 of
Example 36, using
5-methyl-2-propyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridine (169 mg,
0.7 mmol), obtained in Reference Example 5, instead of
5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine.

[0380][step 2] The title compound (compound 38, 170 mg, 58%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-[2-(5-methyl-2-propyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridin-3-yl-
)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
obtained in step 1.

[0384][step 2] The title compound (compound 39, 115 mg, 70%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-[2-(8-oxo-2-propyl-8H-cycloheptaimidazol-1-yl)methyl-10,11-dihydro-5H-
-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (146 mg, 0.34 mmol)
obtained in step 1.

[0388][step 2] The title compound (compound 40, 166 mg, 76%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-
-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (192 mg,
0.44 mmol) obtained in step 1.

[0394][step 2] The title compound (compound 42, 111 mg, 64%) was obtained
in the same manner as in step 3 of Example 1, using
((E)-2-[2-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-di-
hydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (153 mg, 0.37
mmol) obtained in step 1.

[0402][step 2] The title compound (compound 44, 324 mg, 85%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl--
10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (337
mg, 0.74 mmol) obtained in step 1.

[0412][step 2] The title compound (compound 48, 0.16 g, 47%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (0.30 g, 0.72
mmol) obtained in step 1.

[0416][step 2] The title compound (compound 49, 0.26 g, 58%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]m-
ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
(0.40 g, 0.73 mmol) obtained in step 1.

[0420][step 2] The title compound (compound 50, 0.20 g, 60%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (0.30 g, 0.69
mmol) obtained in step 1.

[0424][step 2] The title compound (compound 51, 0.36 g, 70%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo-
[a,d]cyclohepten-5-ylidene]acetonitrile (0.45 g, 1.08 mmol) obtained in
step 1.

[0428][step 2] The title compound (compound 52, 0.11 g, 64%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydr-
o-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (0.15 g, 0.37 mmol)
obtained in step 1.

[0432][step 2] The title compound (compound 53, 0.19 g, 56%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-(2-ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-d-
ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (0.30 g, 0.69
mmol) obtained in step 1.

[0436][step 2] The title compound (compound 54, 88 mg, 53%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[2-(5-ethoxycarbonyl-4-(1-hydroxy-1-methyl)ethyl-2-propylimidazol-1-y-
l)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
(146 mg, 0.3 mmol) obtained in step 1.

[0440][step 2] The title compound (compound 55, 99 mg, 59%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[2-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10-
,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (147 mg,
0.33 mmol) obtained in step 1.

[0444][step 2] The title compound (compound 56, 192 mg, 77%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridin-3-yl)-
methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
(214 mg, 0.45 mmol) obtained in step 1.

[0446][step 1]
(Z)-[2-(5-Methyl-2-propyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridin-3-yl-
)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
was obtained as a crude product in the same manner as in step 1 of
Example 38, using
(Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile (140 mg, 0.54 mmol) instead of
(E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)a-
cetonitrile.

[0447][step 2] The title compound (compound 57, 165 mg, 57%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[2-(5-methyl-2-propyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridin-3-yl-
)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile
obtained in step 1.

[0451][step 2] The title compound (compound 58, 108 mg, 46%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[2-(8-oxo-2-propyl-8H-cycloheptaimidazol-1-yl)methyl-10,11-dihydro-5H-
-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (206 mg, 0.48 mmol)
obtained in step 1.

[0455][step 2] The title compound (compound 59, 126 mg, 56%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-
-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (197 mg,
0.46 mmol) obtained in step 1.

[0467][step 2] The title compound (compound 63, 224 mg, 78%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methy-
l-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (252 mg, 0.60 mmol) obtained
in step 1.

[0471][step 2] The title compound (compound 64, 363 mg, 63%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro--
5H-dibenzo[a,d]cycloheptene (508 mg, 1.2 mmol) obtained in step 1.

[0475][step 2] The title compound (compound 65, 338 mg, 82%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-
methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (362 mg, 0.82 mmol)
obtained in step 1.

[0479][step 2] The title compound (compound 66, 178 mg, 91%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10-
,11-dihydro-5H-dibenzo[a,d]cycloheptene (171 mg, 0.42 mmol) obtained in
step 1.

[0485][step 3] The title compound (compound 67, 137 mg, 82%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl-
)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (146 mg, 0.34 mmol) obtained
in step 2.

[0491][step 3] The title compound (compound 68, 135 mg, 89%) was obtained
in the same manner as in step 3 of Example 1, using
5-cyanomethyl-2-(2-ethoxy-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-1-
0,11-dihydro-5H-dibenzo[b,f]azepine (133 mg, 0.314 mmol) obtained in step
2.

[0497][step 2] The title compound (compound 70, 242 mg, 47%) was obtained
in the same manner as in step 3 of Example 1, using
5-(1-cyanoethyl)-2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-
-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (453 mg, 1.01 mmol)
obtained in step 1.

[0513][step 2] The title compound (compound 82, 94 mg, 40%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-ethyl-4,6-dimethylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-d-
ibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (206 mg, 0.48 mmol)
obtained in step 1.

[0517][step 2] The title compound (compound 83, 65 mg, 41%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibe-
nzo[a,d]cyclohepten-5-ylidene]propiononitrile (139 mg, 0.32 mmol) obtained
in step 1.

[0521][step 2] The title compound (compound 84, 93 mg, 32%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]c-
yclohepten-5-ylidene]propiononitrile (257 mg, 0.62 mmol) obtained in step
1.

[0525][step 2] The title compound (compound 85, 147 mg, 66%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(7-methyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-di-
hydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (196 mg, 0.45
mmol) obtained in step 1.

[0529][step 2] The title compound (compound 86, 53 mg, 18%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,1-
1-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (262 mg,
0.58 mmol) obtained in step 1.

[0533][step 2] The title compound (compound 87, 152 mg, 70%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-
-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (190
mg, 0.43 mmol) obtained in step 1.

[0537][step 2] The title compound (compound 88, 120 mg, 71%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,-
11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (148 mg,
0.34 mmol) obtained in step 1.

[0541][step 2] The title compound (compound 89, 85 mg, 72%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-ethoxy-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-di-
hydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (104 mg, 0.24
mmol) obtained in step 1.

[0545][step 2] The title compound (compound 90, 433 mg, 85%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-d-
ibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (446 mg, 1.10 mmol)
obtained in step 1.

[0549][step 2] The title compound (compound 91, 330 mg, 78%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-ethoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H--
dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (370 mg, 0.88 mmol)
obtained in step 1.

[0553][step 2] The title compound (compound 92, 237 mg, 60%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydr-
o-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (345 mg, 0.83 mmol)
obtained in step 1.

[0557][step 2] The title compound (compound 93, 229 mg, 72%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(7-chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dih-
ydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (280 mg, 0.64
mmol) obtained in step 1.

[0561][step 2] The title compound (compound 94, 154 mg, 73%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(7-chloro-2-ethoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-di-
hydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (186 mg, 0.41
mmol) obtained in step 1.

[0565][step 2] The title compound (compound 95, 283 mg, 83%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(7-chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,-
11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (300 mg,
0.67 mmol) obtained in step 1.

[0569][step 2] The title compound (compound 96, 228 mg, 54%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(4-chloro-2-ethoxybenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibe-
nzo[a,d]cyclohepten-5-ylidene]propiononitrile (368 mg, 0.82 mmol) obtained
in step 1.

[0573][step 2] The title compound (compound 97, 125 mg, 19%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[2-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-
-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (584 mg, 1.30 mmol)
obtained in step 1.

[0589][step 2] The title compound (compound 104, 94.3 mg, 53%) was
obtained in the same manner as in step 3 of Example 1, using
(E)-[3-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-di-
hydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (156 mg, 0.371 mmol)
obtained in step 1.

[0593][step 2] The title compound (compound 105, 64.9 mg, 38%) was
obtained in the same manner as in step 3 of Example 1, using
(E)-[3-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydr-
odibenzo[b,e]oxepin-11-ylidene]acetonitrile (149 mg, 0.367 mmol) obtained
in step 1.

[0597][step 2] The title compound (compound 106, 130 mg, 58%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-[3-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,-
11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (196 mg, 0.445 mmol)
obtained in step 1.

[0601][step 2] The title compound (compound 107, 97.7 mg, 59%) was
obtained in the same manner as in step 3 of Example 1, using
(E)-[3-(2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6-
,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (145 mg, 0.335 mmol)
obtained in step 1.

[0605][step 2] The title compound (compound 108, 26.8 mg, 39%) was
obtained in the same manner as in step 3 of Example 1, using
(E)-[3-(2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11--
dihydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (60.3 mg, 0.144 mmol)
obtained in step 1.

[0609][step 2] The title compound (compound 109, 90.5 mg, 48%) was
obtained in the same manner as in step 3 of Example 1, using
(E)-2-[3-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11--
dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (165 mg, 0.380 mmol)
obtained in step 1.

[0613][step 2] The title compound (compound 110, 126 mg, 64%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[3-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihy-
drodibenzo[b,e]oxepin-11-ylidene]propiononitrile (172 mg, 0.409 mmol)
obtained in step 1.

[0617][step 2] The title compound (compound 111, 296 mg, 66%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[3-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl--
6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (397 mg, 0.873
mmol) obtained in step 1.

[0621][step 2] The title compound (compound 112, 197 mg, 50%) was obtained
in the same manner as in step 3 of Example 1, using
(E)-2-[3-(2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-
-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (351 mg, 0.786
mmol) obtained in step 1.

[0625][step 2] The title compound (compound 113, 78.2 mg, 64%) was
obtained in the same manner as in step 3 of Example 1, using
(E)-2-[3-(2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,1-
1-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (107 mg, 0.247
mmol) obtained in step 1.

[0637][step 2] The title compound (compound 118, 45 mg, 56%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-di-
hydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (70 mg, 0.17 mmol)
obtained in step 1.

[0641][step 2] The title compound (compound 119, 163 mg, 72%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-d-
ihydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (200 mg, 0.46 mmol)
obtained in step 1.

[0645][step 2] The title compound (compound 120, 119 mg, 77%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydr-
odibenzo[b,e]oxepin-11-ylidene]acetonitrile (135 mg, 0.33 mmol) obtained
in step 1.

[0649][step 2] The title compound (compound 121, 96 mg, 90%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,-
11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (94 mg, 0.21 mmol)
obtained in step 1.

[0653][step 2] The title compound (compound 122, 117 mg, 82%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6-
,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (126 mg, 0.29 mmol)
obtained in step 1.

[0657][step 2] The title compound (compound 123, 89 mg, 75%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11--
dihydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (103 mg, 0.25 mmol)
obtained in step 1.

[0661][step 2] The title compound (compound 124, 353 mg, 70%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(2-ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-d-
ihydrodibenzo[b,e]oxepin-11-ylidene]acetonitrile (442 mg, 1.01 mmol)
obtained in step 1.

[0665][step 2] The title compound (compound 125, 268 mg, 64%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(2-ethoxy-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihyd-
rodibenzo[b,e]oxepin-11-ylidene]acetonitrile (369 mg, 0.88 mmol) obtained
in step 1.

[0669][step 2] The title compound (compound 126, 127 mg, 77%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-[8-(7-chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydr-
odibenzo[b,e]oxepin-11-ylidene]acetonitrile (146 mg, 0.34 mmol) obtained
in step 1.

[0673][step 2] The title compound (compound 127, 85 mg, 56%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11--
dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (133 mg, 0.31 mmol)
obtained in step 1.

[0677][step 2] The title compound (compound 128, 118 mg, 67%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihy-
drodibenzo[b,e]oxepin-11-ylidene]propiononitrile (153 mg, 0.36 mmol)
obtained in step 1.

[0681][step 2] The title compound (compound 129, 283 mg, 75%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(7-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl--
6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (334 mg, 0.73
mmol) obtained in step 1.

[0685][step 2] The title compound (compound 130, 191 mg, 85%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-
-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (200 mg, 0.45
mmol) obtained in step 1.

[0689][step 2] The title compound (compound 131, 104 mg, 56%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,1-
1-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (164 mg, 0.38 mmol)
obtained in step 1.

[0693][step 2] The title compound (compound 132, 311 mg, 60%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-
-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (454 mg, 1.01 mmol)
obtained in step 1.

[0697][step 2] The title compound (compound 133, 216 mg, 58%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-ethoxy-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dih-
ydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (329 mg, 0.75 mmol)
obtained in step, 1.

[0701][step 2] The title compound (compound 134, 385 mg, 75%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydrodibenz-
o[b,e]oxepin-11-ylidene]propiononitrile (448 mg, 1.10 mmol) obtained in
step 1.

[0705][step 2] The title compound (compound 135, 324 mg, 73%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-ethoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydrodiben-
zo[b,e]oxepin-11-ylidene]propiononitrile (380 mg, 0.92 mmol) obtained in
step 1.

[0709][step 2] The title compound (compound 136, 377 mg, 82%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydro-
dibenzo[b,e]oxepin-11-ylidene]propiononitrile (400 mg, 0.96 mmol) obtained
in step 1.

[0713][step 2] The title compound (compound 137, 191 mg, 42%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(7-chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihy-
drodibenzo[b,e]oxepin-11-ylidene]propiononitrile (400 mg, 0.91 mmol)
obtained in step 1.

[0717][step 2] The title compound (compound 138, 15 mg, 34%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(7-chloro-2-ethoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dih-
ydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (39 mg, 0.087 mmol)
obtained in step 1.

[0721][step 2] The title compound (compound 139, 214 mg, 56%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(7-chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,1-
1-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (335 mg, 0.74 mmol)
obtained in step 1.

[0723][step 1]
(Z)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiono-
nitrile (150 mg, 0.54 mmol) was dissolved in THF (5.5 mL), and the
solution was added with 2,6-lutidine (0.378 mL, 3.25 mmol), lithium
bromide (282 mg, 3.25 mmol) and methanesulfonic anhydride (236 mg, 1.35
mmol), followed by stirring at room temperature for 16 hr. Ethyl acetate
was added to the mixture, and the organic layer was washed with brine.
The organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give a residue. The obtained
residue and 2-ethyl-4,6-dimethylbenzimidazole (123 mg, 0.71 mmol) were
dissolved in DMF (3.0 mL) and the solution was added with lithium
hydroxide (24 mg, 0.98 mmol) at 0° C., followed by stirring at
room temperature for 2 hr. Ethyl acetate was added to the mixture, and
the organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=7/3-6/4) to give
(Z)-2-[8-(2-ethyl-4,6-dimethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenz-
o[b,e]oxepin-11-ylidene]propiononitrile (219 mg, 93%).

[0725][step 2] The title compound (compound 140, 38 mg, 15%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-ethyl-4,6-dimethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenz-
o[b,e]oxepin-11-ylidene]propiononitrile (217 mg, 0.50 mmol) obtained in
step 1.

[0729][step 2] The title compound (compound 141, 63 mg, 22%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]propiononitrile (248 mg, 0.57 mmol) obtained in step
1.

[0733][step 2] The title compound (compound 142, 67 mg, 23%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-
-11-ylidene]propiononitrile (256 mg, 0.61 mmol) obtained in step 1.

[0737][step 2] The title compound (compound 143, 288 mg, 42%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-ethoxy-4-methylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]propiononitrile (600 mg, 0.61 mmol) obtained in step
1.

[0741][step 2] The title compound (compound 144, 290 mg, 39%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(2-cyclopropyl-4-methylbenzimidazol-1-yl)methyl-6,11-dihydrodibe-
nzo[b,e]oxepin-11-ylidene]propiononitrile (662 mg, 1.53 mmol) obtained in
step 1.

[0745][step 2] The title compound (compound 145, 244 mg, 31%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(4-chloro-2-ethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,-
e]oxepin-11-ylidene]propiononitrile (697 mg, 1.58 mmol) obtained in step
1.

[0749][step 2] The title compound (compound 146, 200 mg, 60%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(4-chloro-2-ethoxybenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b-
,e]oxepin-11-ylidene]propiononitrile (293 mg, 0.64 mmol) obtained in step
1.

[0753][step 2] The title compound (compound 147, 176 mg, 26%) was obtained
in the same manner as in step 3 of Example 1, using
(Z)-2-[8-(4-chloro-2-cyclopropylbenzimidazol-1-yl)methyl-6,11-dihydrodibe-
nzo[b,e]oxepin-11-ylidene]propiononitrile (600 mg, 1.33 mmol) obtained in
step 1.

[0765]Tablets having the following composition are prepared by a
conventional method. Compound S16 (40 g), lactose (286.8 g) and potato
starch (60 g) are mixed, and a 10% aqueous solution (120 g) of
hydroxypropylcellulose is added thereto. According to a conventional
method, the obtained mixture is kneaded, granulated, dried and sieved to
give granules for tableting. Magnesium stearate (1.2 g) is added thereto
and mixed therewith. The mixture is tableted by a tableting machine
(RT-15, manufactured by KIKUSUI SEISAKUSHO LTD.) with a punch having a
diameter of 8 mm to give tablets containing 20 mg of the active
ingredient per tablet.

[0766]Injections having the following composition are prepared by a
conventional method. Compound S13 (1 g) is added to distilled water for
injection and mixed therewith. Hydrochloric acid and aqueous sodium
hydroxide solution are further added to adjust pH of the mixture to 7,
and distilled water for injection is added to make the total amount 1000
mL. The obtained mixture is aseptically filled in glass vials by 2 mL to
give injections containing 2 mg of the active ingredient per vial.